Response to: “Sudden death in SARS-CoV-2 associated polyradiculitis is unlikely due to affection of the phrenic nerve”

We read the paper by Finsterer [1] entitled “Sudden death in SARS-CoV-2 associated polyradiculitis is unlikely due to affection of the phrenic nerve”, which is a comment on our previously presented case [2]. In his paper, he disagreed with the view that the patient died from the affection of the phrenic nerve in the context of GBS.

Several issues in Finsterer’s paper show that he might have misread ours. It seems that he comes from the clinical and not pathology setting, and his interpretation of our presented findings isn’t adequate. In the case description, we presented available, relevant data, not all of the clinical data (which would be impossible). Regarding the autopsy, we gave all the positive findings. That means they would be presented if there were signs of other important and life-threatening conditions. Thus, if the autopsy signs that would be speaking in favor of ischemic heart disease and evident myocardial infarction, heart failure, endocarditis, and cardiomyopathy (including Takotsubo), it would be erroneous and lead to the deception of expert readers. Some of the findings Finsterer mentions are actually described in the paper: focal alveolar edema and fresh focal bleeding do not indicate severe heart failure; signs of moderate to severe coronary atherosclerosis are described, but only with early, non-specific microscopic myocardial injury. These findings do not represent clear autopsy signs of myocardial infarction, nor are sufficient for diagnosing cardiac death in the presented setting.

We also pointed out that “microscopic findings on other internal organs were insignificant”. That includes samples taken from relevant parts of the brain – we took a total of 10 samples. Still, we did not find any relevant findings, including the signs of encephalitis (emphasizing that the neuropathologist was part of the team examining the microscopic findings). The mere presence of light brain edema is a typical autopsy finding and does not indicate or was proven to be a sign of encephalitis. Unfortunately, we did not sample the lower parts of the medulla spinalis nor the roots of cranial nerves X, XI, and XII. However, with all the other examined samples, we don’t think this would be relevant for the cause of death (which is the main task of forensic autopsy), although it would be interesting from the scientific point of view to see if changes were present. This is probably due to our lack of clinical experience, as opposed to the Finsterer’s lack of autopsy pathology experience. Since the patient died in the hospital setting, resuscitation was performed, as Finsterer correctly assumed. However, she was not on a continuous monitoring system, so ECG was not constantly registered. ECG showed only asystole during resuscitation, and no other rhythm disorder was noted. We did not find this relevant for the case presentation.

Again, we presented all the available and relevant clinical data, which means that cerebral imaging with contrast medium, spinal MRI with contrast medium, and additional CSF investigations for SARS-CoV-2, cytokines, and chemokines were not performed during the patient treatment for COVID-19. That also stands for the level of BNP. We agree with Finsterer that these data might be helpful for interpretation, which we would, of course, mention in the paper.

Finally, it seems that Finsterer did not carefully read our paper on several more issues. The patient did not receive immunoglobulin therapy. She was only scheduled for the treatment, but unfortunately, she died before she could receive it. We also stated that the patient was treated “with symptomatic therapy, antibiotic and antiviral therapy, prophylactic doses of low-molecular-weight heparin, rehydration therapy, and oxygen support”. The toxicological screening also showed no significant deviation in drug concentration. We did not find a detailed listing of the drugs relevant to determining the cause of death.

Pathologists work with what they have, and what they have is the morphology – gross and microscopic, with the help of toxicology, some postmortem radiology, where and when available, and not much more. We cannot see the processes, but only their multiple impression on different organs. Determining the cause of death in the pathology setting includes the detailed examination of the external and internal appearances [3]. When there are significant positive findings, it is not hard to link them to the cause of death. When the findings are less clear cut, the alternatives should be discussed, giving a differential diagnosis of the cause of death and detailing the possible sequence of events. If possible, a ranking order of probability of the various alternatives can be offered [3]. In the presented case, we explored the findings, and the most prominent were demyelination and inflammatory infiltration in the peripheral nerves sampled from the cervical and brachial plexuses. We could not entirely exclude the possibility of autonomic dysfunction with heart damage caused by GBS. Still, we had no way of proving it, which we also explicitly stated in the paper. In the absence of another significant potential vital organ injuries, we still believe that it is a fair conclusion that the causes of death were a breathing disorder and the paralysis of the diaphragm due to inflammatory polyneuropathy caused by Guillain-Barré syndrome, initiated by Sars-CoV-2 infection. In forensic terms, demyelination and inflammatory infiltration in the phrenic nerve could be a very strong argument – “a smoking gun.” But, demyelination and inflammatory infiltration in the peripheral nerves sampled from the cervical and brachial plexuses, which give rise to the phrenic nerve, represent sufficiently strong proof – “a positive paraffin test from the hand which held the gun that was fired from” in terms of crime novels.

We find the letter by Finsterer as valuable input in exploring alternatives, which could possibly lead to a better understanding of the clinicians and autopsy pathologists.

1. Declarations

Funding: This work was supported by the Science Fund of the Republic of Serbia, IDEAS Program, Grant No. 7749444 (BoFraM project).

Code availability: Non-applicable.

Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors.

Consent to participate: This study was the result of a routine forensic autopsy and did not compromise any procedure; therefore, obtaining formal consent was not necessary.

Availability of data and material: Data available on request.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.